Molecular mechanisms of T cell infiltration and activation in the CNS during acute inflammation

• Applicant: Privatdozent Dr. Naoto Kawakami
• Subject Area: Molecular and Cellular Neurology and Neuropathology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 564207229

The central nervous system (CNS) is an immune-privileged organ that is separated from the peripheral immune system. However, immune cells can infiltrate the CNS and induce local inflammation, as typically observed in patients with Multiple Sclerosis (MS). MS is an autoimmune disease and accumulating evidence suggests that autoreactive CD4+ T cells play a crucial role in its pathogenesis. Our group has been studying how the autoreactive T cells induce inflammation in the CNS using Experimental Autoimmune Encephalomyelitis (EAE), an animal model for MS. We visualized the infiltration and activation of autoreactive T cells in the CNS using intravital imaging and used a genome wide CRISPR screen to elucidate the essential molecules required for the initial step of lesion formation, the infiltration of autoreactive T cell to the CNS. For inflammatory CNS lesions to form and expand, this initial infiltration of pioneering myelin basic protein (MBP)-specific T cells mainly to the meninges has to be followed by i) the infiltration of further autoreactive T cells to the CNS parenchyma, ii) the invasion of a secondary wave of T cells across the breached blood-brain barrier and iii) the local activation of autoreactive T cells. Here we want to make use of our CRISPR screen approach to identify the molecules that regulate these processes and thus determine how initial sites of T cell infiltration turn into inflammatory CNS lesions. We believe this unbiased approach will lead to novel insights as it will e.g. allow us to reveal shared and stage-specific regulators of T cell infiltration and delineate potential CNS-specific regulators of T cell activation. Our study thus will not only provide a comprehensive understanding of the molecular regulation of CNS lesions formation but can also provide new therapeutic targets that act at different stages of CNS inflammation.

• DFG Programme: Research Grants
• Co-Investigator: Arek Kendirli, Ph.D.